Nephrology Hypertension

Kidney Cancer (Renal cell carcinoma)

Does the patient have kidney cancer (renal cell carcinoma)?

Signs and symptoms

Up to 30% of patients present with humoral or paraneoplastic syndromes; these may include hypertension, unexplained fever, anemia or polycythemia, signs or symptoms of hypercalcemia, cachexia and weight loss, neuromyopathy, and others. When these syndromes are present at diagnosis it usually reflects advanced disease and correlates with a very poor prognosis.

The “classic” presentation of flank pain, hematuria, and palpable abdominal mass occurs in < 9% of patients diagnosed with renal cell carcinoma (RCC). When patients present with this triad, it usually correlates with locally advanced and invasive disease. Patients may present with signs and/or symptoms of distant metastatic disease, humoral or paraneoplastic syndromes, or incidentally when a mass is discovered by radiographic imaging (usually performed for an unrelated issue). Rarely, RCC is discovered by screening in patients at high risk for disease (particularly in familial/genetic syndromes).

Approximately 25-30% of patients present with signs or symptoms of distant metastatic disease; bone, brain and lung are the major sites causing symptomatic disease with distant metastases.

Hematuria is not a common feature of RCC. However tumors invading the collecting system may cause gross hematuria. When gross hematuria is noted, a primary urothelial tumor needs to be considered.

More than 50% of cases of RCC are found incidentally by noninvasive imaging techniques (many times in the work up of unrelated symptom complexes). This mode of detection may lead to the discovery of smaller and more readily treatable tumors. However, based on the incidental finding of a mass by various modes of imaging, each with its own sensitivities and specificities, these small masses may require further work up to either confirm or rule out the diagnosis of renal cell carcinoma.

Physical exam

Physical exam has a limited role (particularly with small and early stage tumors). Large (especially lower pole) tumors may be palpable on abdominal/flank exam; cervical lymphadenopathy may be present; varicocele in men (more commonly with tumors of the left kidney); lower extremity edema or ascites (in the case of vena cava invasion of tumor).

History

The key elements of the history include questions that may elucidate key features of either locally invasive disease, humoral or paraneoplastic syndromes, distant metastatic disease, or venous obstruction. Ask about a history of pain (flank, abdominal, back), hematuria, weight loss, unexplained fever, weakness, or fatigue; a history of scrotal swelling in men, ascites, or lower extremity edema could indicate central venous obstruction; bone pain, respiratory symptoms, or neurologic symptoms may reflect distant metastatic disease.

Pre-existing conditions which may be associated with kidney cancer must be reviewed including a history of hypertension, obesity, or chronic kidney disease. Exposure to agents thought to be associated with the development of kidney cancer should also be reviewed (tobacco use, phenacetin, trichloroethylene).

A family history of RCC or syndromes associated with RCC is important in the workup. Von Hippel Lindau (VHL) is an autosomal dominant disease with a risk of up to 60% for developing RCC. Multiple and bilateral tumors may develop. Hereditary papillary RCC is a familial syndrome associated with activating mutations of the MET protooncogene. This syndrome is associated with a high malignant potential and development of RCC as early as age 18. A history of RCC at an early age in family members should raise suspicion for this familial syndrome. Although tuberous sclerosis complex (TSC) is weakly associated with RCC, when it occurs it is usually multifocal and presents at an early age.

Differential diagnosis considerations

Once a mass or complex cystic lesion is discovered (many times incidentally by ultrasound or computed tomography [CT] scan), the goals are to determine whether the lesion is benign or malignant and to determine the extent of disease. Based on the features of the lesion on imaging (See section on pm “Imaging techniques”) and the clinical setting, the following entities may be considered in the differential diagnosis.

Cystic disease

Simple cyst – most common renal mass in adults; arise from cortical tubules; enlarge with time and may cause compression of adjacent structures, cause hematuria, develop septations, and rarely become infected (See “Evaluation of cystic masses”)

Oncocytoma – solid benign tumor; cannot be distinguished from RCC by imaging; homogeneous low enhancement on CT; may have a central scar; many get excised due to appearance almost indistinguishable from RCC.

Angiomyolipoma – may occcur sporadically (especially in females and up to 80% in tuberous sclerosis); may be associated with neurofibromatosis I and von Hippel-Lindau; risk hemorrhage when larger than 4 cm; on ultrasound well marginated hyperechoic due to fat content; on CT measure < 10 hounsfield units (HU) on non-enhanced images; usually are vascular and will enhance; can also be distinguished by their fat content; on magnetic resonance imaging (MRI) have high T1 signal.

Metanephric adenoma – rare, benign tumor that has histologic similarity to nephroblastoma (Wilms tumor); may be associated with “classic” signs and symptoms of RCC (pain, hematuria, palpable mass); can be associated with polycythemia; half are discovered incidentally; essentially indistinguishable from RCC on radiologic imaging.

Pseudomass – (column or Bertin)-can be confusing on ultrasound imaging; normal renal cortex is interposed between renal pyramids and extends into central sinus; clarified on contrast CT as enhancement is the same as the “normal” kidney tissue.

Malignant tumors

*RCC (primarily adenocarcinomas of the clear cell, papillary, or chromophobe type) – most common primary renal malignancy (approximately 90%); on imaging appears as a focal mass centered in the cortex distorting renal margins; ultrasound appearance can be confusing with 50% hyperechoic, 30% isoechoic, and 20% hypoechoic with necrosis; CT (gold-standard test) usually shows slightly hyperdense compared to nomal parenchyma (precontrast); heterogeous enhancement greater than 15-20 HU but less than surrounding normal tissue; may contain punctate, amorphous, linear or peripheral calcification; cystic RCC described by Bosniak classification; MRI appearance is mildly hypointense to renal cortex on T1 and slightly increased signal on T2 images; most show enhancement with gadolium on T1; enhancement of septations or solid components also consistent with malignancy; hypointense pseudocapsule may be seen around the periphery. THESE TUMORS WILL BE THE MAJOR FOCUS OF THIS SECTION.

Transitional cell carcinoma – approximately 10% of malignant renal tumors; uroepithelial tumors most common in bladder, ureters, and kidney in decreasing frequency; most common imaging appearance is a small hypodense or echogenic lesion in the collecting system; may also be a locally aggressive infiltrative renal mass originating centrally and expanding the kidney with preserved cortical appearance; may also appear as thickening of the collecting system uroepithelium or ureteral wall

Lymphoma (rare)- usually presents as part of systemic disease with non-Hodgkins having more renal involvement than Hodgkins; most present as multiple focal “solid” masses (mostly bilateral) with enhancement less than normal tissue; may also present as a renal hilar mass invading the kidney, a rind or perinephric soft tissue, or diffuse infiltration expanding and enlarging the kidney

Metastasis (rare)- often multiple and bilateral but may also be solitary lesions mimicking RCC; most primaries are lung, colon, breast, and melanoma (therefore, a known primary of any of these types should raise suspicion); hemorrhagic metastasis may be seen with melanoma, pheochromocytoma, and leiomyosarcoma

Wilm’s tumor (primarily in children; not to be discussed in this section)

Others

Infection (abscess)- poorly marginated on ultrasound; debris and fluid filled cystic structures with increased through-transmission; on CT the kidney may appear enlarged with perinephric inflammatory changes and thickening of Gerota’s fascia; hypodense center with thick and irregular ill-defined rind of enhancing tissue +/- septations; may be difficult to distinguish from necrotic renal tumor; clinical course and presentation will usually distinguish these.

Infarction or perfusion defect

Who gets kidney cancer?

The increased incidence of disease in the United States in last two decades is likely due to more incidental tumors being found. Several risk factors have been associated with kidney cancer. Renal pelvic tumors (mostly transitional cell in origin) have been clearly associated with cigarette smoking and the use of phanacetin-containing analgesics (no longer available in the US). These tumors account for less than 10% of kidney cancers. Data from large registries on kidney cancer generally contain a mix of RCC and renal pelvic tumors.

However, several trends have been established in the epidemiology of kidney cancer. The increase in cases has included men, women, black, and white populations essentially without significant disparity. There is an approximately 2:1 male:female ratio.

Smoking: compared to never smokers there is a 50% increased risk in male and 20% increased risk in female smokers (1); dose-dependent increase in risk; suspected chronic exposure to hypoxia and carbon monoxide with cumulative DNA dmage due to chronic exposure to toxins

Hypertension: possible dose-dependent relationship; duration of hypertension may increase risk; seems to be independently associated although many cases also associated with obesity; thought to be due to chronic renal hypoxia, lipid peroxidation, and increased formation of reactive oxygen species

Reproductive hormones: possible relationship with less risk in nulliparity compared to multiparity

ETOH: inverse relationship; estimated 28% risk reduction in those drinking the equivalent of >/= 15 gm/day (regardless of the type of beverage)

Kidney disease:

Acquired renal cystic disease (ARCD):

ARCD is associated with CKD, ESRD, and kidney transplantation. It is a risk factor for RCC (3-5).

CKD: 7% incidence of ARCD

ESRD: 22% incidence of ARCD; > 10 years of ESRD the incidence is 50-80%

Post-kidney transplant:

The risk for ARCD is according to years of ESRD (as noted above).

The 3 year cumulative risk of RCC is approximately 2.2% (mostly in the native kidneys).

The risk of RCC in patients with ARCD is 5x greater than in the general population.

***There is no consensus guideline on screening for RCC in patients with ARCD as there are no consistent proven longterm outcome benefits. There may be a reduction in cancer-specific risk of death in young patients with ARCD who have minimal comorbidities. In this specific population one could consider periodic screening with a standard CT protocol.

Environmental and occupational factors: An elevated risk of RCC has been linked to certain occupations and exposure to particular industrial agents. In general, however, RCC is not considered an occupational disease.

Trichloroethylene (TCE):

TCE is the most extensively examined chemical associated with RCC. It is used as a degreaser and chemical additive and has become a very important and growing environmental contaminant. The mode of action of TCE in its relationship to RCC is unknown.

Cadmium and uranium have only inconsistently been linked to RCC risk.

Exposures to arsenic, nitrate, and radon in drinking water have not be linked.

Genetic disorders: Kidney cancer comprises a number of different types of cancer, each associated with different gene abnormalities with different histology, clinical course, and response to therapy. There are seven known “kidney cancer genes”: VHL (von Hippel-Lindau), HGF-MET (hepatocyte growth factor receptor; a proto-oncogene), FLCN (a novel gene on the short arm of chromosome 17 associated with Birt-Hogg-Dube syndrome), TSC1 (tuberous sclerosis gene 1), TSC2 (tuberous sclerosis gene 2), and 2 genes enzymes in the tricarboxylic acid cycle, FH and SDH (fumarate hydratase and succinate dehydrogenase).

Mutations in each of these genes results in dysregulation of metabolic pathways crucial to oxygen, iron, energy or nutrient sensing. The discovery of such genes has led to a robust explosion of investigations targeting kidney cancer as a disease of cell metabolism. This has in turn led to the development of several agents targeting such pathways in the treatment of RCC.

The four most well described types of inherited kidney cancer (Table 1) include von Hippel-Lindau, hereditary papillary RCC, hereditary leiomyomatosis with RCC, and Birt-Hogg-Dube syndrome.

Molecular pathogenesis of clear cell renal cell carcinoma

Clear cell RCC is the best studied form of RCC. The development of this type of tumor involves several complex physiologic pathways which culminate in the upregulation of angiogenic and proliferative factors, of which vacular endothelial growth factor (VEGF) is the most important. The VHL gene is directly linked to the pathways leading to increased angiogenesis and tumor development. Many tumors over express VEGF-A primarily in response to hypoxia in the core of the tumor where the vascular supply may be oustripped. RCC is the only cancer with an oncogenic event that directly upregulates VEGF production, leading to tremendous VEGF levels. This is because each cell has the underlying molecular drive to produce VEGF, even in normoxic conditions.

Under normal oxygen conditions, the VHL gene product (pVHL) promotes the degradation of hypoxia-inducible factor (HIF). HIF is an inducible transcription activator of hypoxia-responsive genes including VEGF. In ccRCC abnormalities in the VHL gene result in loss of function of pVHL, a decrease in HIF, and ultimately an upregulation of VEGF along with other regulators or angiogenesis and proliferation. This ultimately contributes to tumor growth and survival. The discovery of these pathways has led to the development of agents that block the production or activity of VEGF and decrease tumor growth or result in regression. Anti-VEGF antibodies, medications that target the VEGF receptor, and the inhibitors of the mammalian target of rapamycin (mTOR inhibitors) have all shown efficacy in the treatment of RCC (See Treatment section: Targeted therapies).

What tests to perform?

Much of the testing performed in the workup of RCC is in an effort to determine the stage of disease which impacts treatment decisions and determines prognosis. Although imaging techniques have improved significantly and may highlight findings suggestive of RCC, there are limitations. The only definitive means of making a diagnosis is with tissue confirmation, either by biopsy or surgery.

Laboratory data

Laboratory data is generally obtained to be used in nomograms or algorithms to determine the stage and prognosis. These have been developed through population studies and correlated with outcomes (See section on Predicting prognosis). The following tests should be obtained: complete blood count (CBC), Blood urea nitrogen (BUN), creatinine, liver function tests (LFT), serum calcium level, lactate dehydrogenase (LDH), alkaline phosphatase, coagulation studies, urinalysis (and urine cytology if hematuria is present).

CBC: evaluate for anemia, erythrocytosis, or thrombocytosis which may be paraneoplastic findings and are associated with worse outcomes; also necessary to make treatment decisions

BUN and creatinine: an assessment of renal function is necessary to make treatment decisions (particularly nephron sparing options in the setting of reduced renal function)

LFTs: elevated levels may be associated with liver metastases or as a paraneoplastic syndrome

serum calcium: elevated serum calcium may be associated with bone involvement or as a paraneoplastic syndrome

alkaline phosphatase: may be elevated due to bone metastasis or as a paraneoplastic syndrome

urinalysis: hematuria may indicate a centrally located tumor and may help differentiate urothelial tumors from RCC (especially if associated urine cytology is positive)

Imaging techniques

CT scan of the abdomen and pelvis with and without IV contrast is the gold-standard imaging modality for evaluating renal tumors (solid or cystic). A properly performed and constructed CT scan is usually diagnostic (particularly for larger lesions). In addition, most clinical studies have used CT scanning as the standard for evaluating stage of disease, determining prognosis, developing follow-up protocols during and after treatment, and for surveillence of disease in conservative management approaches.

Ultrasound is an excellent method for discerning cystic from solid lesions.

MRI may be used in situations where iodinated contrast for CT is contraindicated (such as in patients with high risk for contrast induced nephropathy or with low GFR). MRI is also the test of choice to evaluate the extent of central venous involvement of disease (vena cava invasion/tumor extension).

CXR (or CT) is used for staging purposes in the work up to evaluate for lung metastasis.

Controversies and limitations in diagnostic imaging tests

There are some limitations to the use of certain diagnostic tests. Due to the nature of RCC, particularly the very slow growth rate, these tumors may not exhibit features “typical” of other malignancies (irregular borders or necrosis). One of the major reasons for imaging is to predict the malignant potential of a lesion. The malignant potential may be dictated by the size of the tumor. In the general population, most lesions < 1.5 cm are either cystic or benign. Whereas, in tumors > 4 cm more than 90% are malignant. The sensitivity of both ultrasound and CT scan may be limited by tumor size. Whereas CT scan demonstrates 75% sensitivity in predicting malignancy in tumors 1.0-1.5 cm, ultrasound has only 28% sensitivity. The sensitivity decreases for both studies when the size of the tumor is less than 1.0 cm.

The presence of CKD may present another limitation to radiographic testing. The use of certain forms of gadolinium for MRI and MRA in patients with kidney disease has been rarely associated with a painful, debilitating, and difficult to manage complication referred to as nephrogenic fibrosing dermopathy. Because of this, there is a black box warning with regard to the use of these agents in patients with reduced GFR. The use of iodinated contrast for CT enhancement may be associated with contrast-induced nephropathy (CIN). Patients with a low GFR should be assessed and measures to reduce the risk of CIN should be undertaken prior to contrast administration. Close follow-up by monitoring renal function should continue for 72 hours after the study in high-risk patients.

Biopsy

Obtaining tissue for pathologic evaluation is essential in the management of RCC. Most tissue evaluation historically has been on the basis of nephrectomy and partial nephrectomy samples. However, with newer modalities of treatment (see Managment section), where nephrectomy may not be performed (conservative surveillence, ablative and targeted therapy), biopsy may be necessary to confirm the diagnosis and determine the histologic subtype and grade.

Incidental masses are being discovered at an increasing rate and approximately half of these are being found in patients older than 65 years of age. Because these patients may have multiple comorbidities prohibiting a surgical approach, tissue confirmation and histologic staging are necessary to plan therapy. In some cases. ablative therapy or surveillence may be the chosen approach if surgery is prohibitive.

With advances in biopsy technique, tissues preparation, histologic and molecular technique, and standardization of interpretative approaches, the accuracy and clinical utility of biopsy has improved significantly. Recent reports quote up to 90% accuracy and tissue adequacy with core biopsies in the hands of experience operators and pathologists.

If a metastatic lesion is accessable for biopsy, it may be targeted for diagnostic purposes.

Limitations to biopsy:

Some data suggest up to 20-25% inconclusive results (of which, up to 50% may ultimately be malignant).

Small lesions may result in less adequate sampling.

It is necessary to have dedicated pathology services with experience in protocols for analyzing RCC and other urologic pathologies.

Summary of biopsy recommendations: If a mass has a high likelihood of being malignant based on the features of imaging, then determine if the patient is a surgical candidate (particularly for stage I-III tumors). If the patient is a surgical candidate, pathology can be obtained at the time of surgery (partial or radical nephrectomy). If the patient is not a candidate for surgery, decide if they are a candidate for ablation therapy (based on tumor size, location, and clinical features such as comorbidities). If YES, then biopsy prior to ablation. If NO, then proceed to conservative surveillence. In advanced disease, biopsy accessable metastatic lesions to make tissue diagnosis. In patients with another known primary tumor, biopsy newly found kidney masses to determine if it is a new RCC or metastatic lesion.

Summary of diagnostic testing

A primary workup for RCC is rare and many tumors are found incidentally. Rare situations including familial disorders require screening for RCC. When a lesion suspicious of RCC is found appropriate steps should be taken to narrow down the diagnosis. Imaging tests are not 100% diagnostic and tissue confirmation should be pursued. Lab testing and further radiologic testing is generally performed to determine the clinical stage of disease. Based on the clinical stage of the disease, prognostic scoring can be applied and a treatment plan accordingly implemented. (SEE BELOW FOR CLINICAL STAGING).

CT scanning protocols

Because of the slow-growing nature of RCC and lack of typical features of malignancy, specific protocols for imaging by CT scan have been developed. The consistent use of these protocols with standard techniques for data acquisition, reconstruction, and display have led to an improvement in diagnostic potential for this mode of imaging. The imaging technique is referred to as multidetector CT (MDCT).

Acquisition Phases of contrast CT imaging:

Unenhanced

Corticomedullary

Nephrographic

Excretory (delayed)

In the corticomedullary phase cortical and arterial structures reach peak enhancement with best corticomeddullary differentiation of renal structure. This phase is most useful for surgical planning where vascular “mapping” can be achieved before a partial nephrectomy. The nephrographic phase has more sensitivity for detecting both cortical and medullary masses compared to the corticomedullary phase. The combination of corticomedullary and nephrographic phases yields the best rate of kidney cancer detection, characterization, and staging.

The phases of MDCT may help in the differential diagnosis of kidney masses. Clear cell RCC is very vascular and enhances maximally in the corticomedullary phase where chromophobe and papillary tumors enhance to a lesser degree in the early phase. Medullary tumors tend to enhance maximally in the nephrographic phase

Reconstruction techniques are used to construct 3-dimensional representations which may significantly improve the characterization of smaller kidney lesions.

Unenhanced (pre-contrast administration)

Calculus

Cystic versus solid mass

High-density renal cyst

Identify location of kidneys

Corticomedullary (25-50 seconds post-contrast)

Evaluate arterial structures

Preoperative planning for nephron-sparing surgery

Define tumor neovascularity

Changes in perfusion

Detect masses

Pyelonephritis

Nephrographic (60-140 seconds post-contrast)

Renal lesion detection (cyst or solid)

Characterize lesion density

Pyelonephritis

Tumor invasion (in transitional cell carcinoma)

Changes in perfusion

Renal vein and vena cava thrombus

Excretory (5-8 minutes post-contrast)

Transitional cell carcinoma

Collecting system obstruction

Pyelonephritis

Changes in perfusion

Measure lesion de-enhancement (if no unenhanced phase)

Evaluation of cystic masses

The Bosniak classification has been developed and refined to help more accurately characterize renal cystic masses and predict their malignant potential. As with solid renal masses, CT scan is the gold standard for radiographic evaluation of cystic renal masses. With increased abdominal imaging over the past two decades there has been an increase in the discovery of aysmptomatic renal cysts. Approximately half of people older than age 50 may have at least one renal cyst. Most of these are simple and benign. However, certain cystic features are associated with an increased potential for malignancy.

Simple cysts: These are, benign, unilocular, fluid-filled, and arise from the renal cortex. On CT scan they are sharply marginated, round, smooth, and homogeneous with a thin surrounding wall. They are the density of water, or 10-20 Hounsfield units (HU is the standard measure of density used for CT imaging). There is no enhancement with contrast administration.

Complex cysts: These are cysts that contain calcifications, septations, thickened or irregular walls, or an increase in density with contrast administration. With a greater degree of complexity, there is an increased risk for malignant potential. In addition to these complex features, several other factors should raise the suspicion for malignancy:

size > 10 cm

any localized contrast enhancing thickening of the wall

heterogeneous cyst contents

irregularly or poorly defined implantation into the kidney

Approximately 5-7% of RCC are cystic tumors. They generally have a slower rate of growth and more favorable pathologic stage and histologic grade, which results in a better prognosis.

The Bosniak classification of renal cysts assigns a category depending on the CT radiographic features of a cyst (including wall characteristics, septae, fluid characteristics, calcifications, and size).

Class 1: A simple benign cyst with a hairline thin wall; no septa, calcifications or solid components; measures as water density of less than 20 HU; no enhancement with contrast administration

Class 2: A bennign cyst that may contain a few hairline thin spta; fine calcification may be in the cyst wall or septa; uniformly high-attenuation lesions less than 3 cm; sharply marginated without enhancement

Class 2F: These may contain more hairline thin septa than in category 2; minimal enhancement and/or thickening of hairline thin septum or wall; may contain calcification that might be nodular and thick but there is no contrast enhancement; well marginated

Class 3: Indeterminate cystic masses that have thick irregular walls or septa with some enhancement

Based on the Bosniak category, a risk for malignancy may be estimated. Several studies have correlated Bosniak categories with pathologic findings and clinical outcomes. The sum of the data would suggest that almost all category I lesions are benign and almost all category 4 lesions are malignant. In addition, approximately 1/3-1/2 of category 3 lesions are malignant and should be managed as such. If unsure whether a lesion is category 2 or 3, one should assume 3. To further delineate category 2 and 3 a biopsy, cyst aspiration, and PET scan may be considered. PET scan has an excellent negative predictive value. However, a good quality CT scan should be able to discern category 1-4 with near 100% accuracy.

What is the natural history of renal cell carcinoma?

Studies of the natural history of RCC are limited and exhibit selection bias as they comprise groups of patients that were likely unfit or unwilling to undergo definitive surgical therapy for their disease. However, putting together the data from the largest studies has yielded some interesting trends regarding the natural history of untreated renal masses.

Tumor growth rate

Small tumors (1.5-4 cm) demonstrate an average growth rate of approximately 0.3 cm per year. Up to 1/3 of tumors may have no growth during 2-3 years of follow up. In cases where tissue was ultimately obtained, 90% are RCC while the others are benign (see differential diagnosis section). There is no significant difference in growth rate between malignant and benign masses. In general, the size of the tumor at the time of presentation does not predict growth rate. Larger tumors (median 6 cm) also have a slow growth rate (in some series a mean rate of growth of approximately 0.4 cm per year).

Metastatic potential:

The size of the tumor correlates with metastatic potential. In small tumors (1.5-4 cm) there is an exeedingly low rate of metastasis with a rate at 2-3 years of < 1%. Tumors > 3 cm tend to demonstrate a greater metastatic potential with up to 25% metastasis when greater than 3 cm in diameter.

Natural history by histologic subtype:

There is no good evidence to suggest differential growth rates based on histology of renal tumors. In fact, benign tumors have been found to grow at similar rates as malignant RCC.

*Because of these observations regarding the natural history, growth, and metastatic potential of renal tumors, several surveillence protocols have been suggested for patients who are unfit or unwilling to undergo intervention. A summary of surveillence protocols will be provided in a later section.

How should patients with renal cell carcinoma be managed?

Decisions regarding therapy are based on disease-specific factors (histology, tumor stage and grade) and patient-specific factors (performance status, comorbidities, and patient wishes). Currently, several therapeutic options exist for patients with RCC. In addition, several European and North American guidelines have been developed, particularly for the treatment of advanced RCC (SEE BELOW).

Surgery

Laparoscopic or open approach depends on the nature of the tumor and surgeon preference and expertise:

Partial nephrectomy- limited resection of the portion of the kidney where the mass is (also refered to as “nephron-sparing” surgery)

Simple nephrectomy- removal of the kidney without node or adrenal resection

Cytoreductive nephrectomy- removal of the kidney in the setting of advanced stage IV disease where cure is not expected to be achieved

Surgical resection of localized disease remains the treatment of choice for either cure or long-term disease-free survival. Nephrectomy is recommended in patients with stage I-III disease. The degree of resection is dictated by the extent of disease and location of the tumor. Historically, partial resection was done in patients with a solitary kidney or severe CKD where a radical nephrectomy would render a patient functionally anephric. With recent data suggesting that nephrectomy-induced CKD is associated with an increased risk of all-cause and cardiovascular death, nephron-sparing procedures should be considered when at all possible.

However, it should also be noted that CKD stage III or greater will develop in approximately 1/3 of patients undergoing partial nephrectomy. This may occur even with a relatively preserved preoperative GFR (> 60 ml/min/1.73 m2). For patients with lower renal function preoperatively, the risk is greater for post-nephrectomy CKD progression. Therefore, patients with RCC undergoing radical or partial nephrectomy should be evaluated and monitored by a nephrologist. Preoperative renal function should be assessed and the risk of progression and the consequences should be discussed with all patients undergoing partial or radical nephrectomy.

In some cases a more extensive surgery may be unavoidable. The ipsilateral adrenal gland may need to be removed if the tumor is adjacent to assure removal of all tumor material. When a mass is central, involving or adjacent to the hilum and vascular structures, partial nephrectomy may not be achieved and the entire kidney may need to be removed. In patients who are not surgical candidates (due to age, debility, comorbidities) or refuse surgery, alternative management needs to be considered. This may include ablation therapy, or surveillence.

Summary of surgical recommendations based on TNM stage of disease (see section on TNM staging) (adapted from the NCCN guidelines on kidney cancer)

In patients with stage IA (T1a) disease, a partial nephrectomy is preferred when technically feasible. Other options include surveillence (in patients with significant comorbidities or decreased life expectancy) or ablation(see below for details). In stage 1B (T1b) disease partial or radical nephrectomy is considered standard of care.

In stage II and III disease, radical nephrectomy is recommended given the higher rate of disease progression and recurrence in these tumors. When the vena cava is involved or there is extension into the right atria the surgical mortality can be up to 10%. Cardiovascular surgery involvement is required.

In stage IV disease surgical resection is referred to as cytoreductive and is done primarily to reduce the tumor burden. Metastasectomy can be performed in select cases where a patient presents with a resectable primary tumor and solitary metastatic lesion amenable to resection. In addition, metastasectomy may be done after nephrectomy when a single site of metastasis occurs. Most patients who undergo metastasectomy ultimately have recurrence at the primary or metastatic site. Palliative nephrectomy may be done for local (pain or bleeding) or systemic symptoms of the disease. In some cases, cytoreductive nephrectomy may be done prior to immunotherapy (particularly with interferon-alpha) where results favor the combined therapy. However, in the era of targeted molecular therapy this has become a controversial issue and trials are ongoing to resolve the controversy (to be discussed further).

Ablation Therapy

Clearcut indicationsor these procedures in the treatment of RCC have not been established. There is no longterm comparative efficacy data with surgical excision. Patient selection is key. In patients who have tumor characteristics optimal for resection but surgery is contraindicated or refused, ablation may be the best therapeutic option (other than surveillence). In addition, these methods can be used in patients where multiple tumors are present and a nephron-sparing approach is needed. Patients should be medically stable, without irreversible coagulopathy, and should have a life expectancy > 1 year and no distant metastatic disease.

The general concept is to create an extreme of temperature (heat or cold) in a minimally invasive manner to produce tumor cell death. Both tumor and patient factors guide the decision to use ablation. The production of extreme temperatures is limited to a small area and therefore only small tumor can be treated with these methods (< 4 cm). In addition, a margin of treatment (ablation margin) around the tumor should extend 0.5-1.0 cm. This allows for the probe to be maneuvered into place and assures the entire tumor is treated. Because of this, tumors near vital structures (collecting system and vascular structures) are not good targets. Peripheral tumors are the best targets. Because this procedure is used in small tumors and many small tumors are benign, a tissue diagnosis prior to treatment is necessary. Tumors less than 3 cm may only require one treatment, whereas tumors > 3 cm may require repeated treatments.

These procedures are performed by urologists and interventional radiologists. They are generally performed under conscious sedation but may require general anesthesia.

Cryoablation- a process where liquid nitrogen or Argon is injected into a tumor to produce ice crystals which disrupt cell membranes resulting in cell death and apoptosis. This tends to be a laparoscopic procedure requiring general anesthesia, and may be more involved than RFA.

Radiofrequency ablation (RFA)- a process where high-frequency alternating current (460-500 kHz) is used to produce a local rise in temperature resulting in protein destruction and cell death. In most cases this procedure can be performed percutaneously under conscious sedation. A need for repeat procedures occurs more often with this approach. However, in approximately 95% of cases this is a percutaneous procedure and the hospital stay averages 1.4 days vs 3 days with cryoablation.

Side effects: As with any invasive procedure, infection and bleeding may occur. Also, a self-limited flu-like syndrome has been described. The overall incidence of serious side effects is low.

Surveillence after ablation therapy: CT scan with contrast enhancement is the test of choice in monitoring effecacy of treatment and recurrence of disease. Usually a CT is done at least a month after therapy. Areas of viable tumor are noted as nodular or crescent-like rims of enhancement in the area of the oringinal tumor. A monitoring schedule of 3-6 months, 12 months, 18 months, 24 months, and yearly thereafter is suggested. If a recurrence is diagnosed, repeat procedures can be done (based on original criteria for candidacy for this type of therapy).

Results: Mean 5 year recurrence-free survival is estimated at 90% for both procedures when patients are selected as outlined above. Local tumor progression is more common with RFA but the rate of progression to metastatic disease is equal for both procedures.

Immunotherapy

Historically, these therapies were important in the management of RCC. However, with the introduction of molecular targeted therapies and the lower side effect risk and ease of administration (some oral), immunotherapy has become mostly a 2nd and 3rd line option in select patient populations.

Interleukin-2 (IL-2) is the only form of immunotherapy that has been shown to induce a durable response in advanced RCC. However, this is only seen in a very select patient population and in approximately 9% of those treated. The best experience has been in patients who go onto surgical resection after IL-2 therapy. It is unknown how IL-2 works to treat RCC. The best response is in the high-dose regimen which is also associated with many side-effects, limiting the overall use of this therapy. Major side-effects include hypotension, arrhythmias, flu-like syndrome with fever and chills,neurotoxicity, edema, elevations in transaminases, peripheral edema, increased creatinine, and rash. The limitations to the use of IL-2 include availability of the drug, tolerability, and limited efficacy in certain cases (large tumor burden, multiple metastatic sites, liver and lymphatic involvement, and a period of progression-free-survival less than 1 year prior to instituting therapy).

Interferon-alpha (IFN-α) has been used as a single agent with limited benefit in advanced RCC. A response may be seen in up to 15% of patients but tends to be partial and short-lived. The mechanism of action in the treatment of RCC is unknown. Due to the extensive side effect profile and limited efficacy, this therapeutic option has fallen out of favor as a single agent. However, in patients with metastatic disease and good to intermediate prognosis, combination therapy with the VEGF antibody bevcizumab is considered a first-line option by most gnational guidelines. In some guidelines it is suggested for patients with a poor prognosis as a second-line option. With the introduction of molecular targeted therapy the use of IFN-α has decreased. (ALSO SEE SECTION ON TREATMENT GUIDELINES)

Some studies have suggested:

Targeted Molecular Therapy

With the discovery of complex pathways involving HIF, VEGF, and other angiogenic and proliferative cytokines, the development of agents targeting these molecules has led to a new kind of therapy for cancer. Further sections will review the recommendations for the use of these agents in several protocols. These drugs are used in the treatment of advanced RCC. However future studies may involve patients with less advanced disease as well as patients in high risk categories undergoing surgical treatment where adjuvant molecular targeted therapy may improve long-term outcomes. Although most clinical data has been derived from patients with ccRCC, reports of efficacy in papillary and chromophobe tumors has been seen in some studies.

Vascular endothelial growth factor (VEGF) inhibitors:

Bevacizumab is a humanized monoclonal antibody against VEGF. Based on its ability to bind VEGF and prevents its binding with the VEGFr this agent is targeted to reduce tumor angiogenesis and proliferation. Although it results in an upregulation of VEGF, at clinically relevant doses it is able to bind these levels as well. At higher doses as a single agent, this medication has been associated with thrombotic thrombocytopenic purpura (TTP). Therefore, the lower dose in combination with IFN-α is the prefered regimen suggested in most treatment guidelines. Due its ability to reduce smooth muscle nitric oxide production, bevacizumab is associated with the development or exacerbation of hypertension. In combination with IFN-α it has been associated with improved progression-free survival (PFS) and an improved objective tumor response rate in patients with advanced RCC.

Sunitinib and Sorafenib are in the category of agents called kinase inhibitors. They not only bind several different subtypes of the VEGFr but also target the platelet-derived growth factor receptor (PDGFr) which is involved in the recruitement of pericytes which help develop spouting tumor vessels. Because these agents inhibit a broad range of kinases at the doses needed for clinical response, several toxic effects may be observed. Between 20-25% of patients may develop hypertension while being treated. Interestingly, some studies have associated the development of hypertension with better cancer-associated outcomes. Thyroid dysfunction is relatively common and both hypothyroid and hyperthyroid cases have been described. LFTs should be monitored as hepatotoxicity has been seen in some cases. Hand-foot syndrome is common and may cause painful desquamation in some patients.

Mammalian target of rapamycin (mTOR) inhibitors:

These agents are involved in interupting pathways that regulate cell growth, metabolism, proliferation, and motility. As with the VEGF-inhibiting agents, pathways associated with responses to hypoxia and energy metabolism are affected. The mTOR inhibitors bind to the intracellular protein FKBP12 and the complex then binds to mTOR at the rapamycin binding domain. This process results in the inhibition of multiple kinase activities. The process is highly selective and there are no other known receptor targets for rapamycin and its analogues. Although further studies will lead to better patient selection and likely result in more consistent outcomes, several very important clinical outcomes have been described.

Temsirolimus may be first-line treatment in patients with advanced disease and poor prognosis. Since the side effect profile is relatively benign, it may provide reasonable improvements in short-term quality of life in these patients.

Everolimus has been shown to improve progression-free survival in patients with advanced disease who progressed on Sunitinib or Sorafenib.

***Further clinical experience with these agents is needed to more specifically target particular patient populations that will benefit most. Also, the use of combinations of medicine and sequencing regimens may have a role in future studies and in clinical practice. The goals would be to improve efficacy, reduce resistance to therapy, and reduce side effects.

Surveillence

Protocols have been developed for monitoring patients for recurrence or metastasis after surgical treatment for localized disease. More rigorous surveillence is suggested in higher risk disease. Two widely accepted surveillence protocols are generally used in clinical practice.

The UCLA integrated staging system (UISS)-based system divides patients into 3 risk categories. Each category follows its own set of surveillence testing which varies in terms of schedule and degree of testing (history, exam, lab studies, imaging).

The National Comprehensive Cancer Network NCCN)-based protocol uses the TNM stage at the time of diagnosis to guide surveillence. Two sets of recommendations are given: one for stage I and II, and a more intense protocol for stage III. It should be noted that there is no evidence suggesting an increased in survival when active surveillence is implemented. Because of the relative simplicity of the NCCN protocol and lack of comparative data between the two protocols, the NCCN will be summarized here.

Radiation (generally only used for the management of bony metastases where palliation is necessary)

Clinical trials: Patients who may not be candidates for currently accepted treatment protocols, based on tumor or clinical factors, may be suitable for entrance into one of many clinical trials.

What happens to patients with renal cell carcinoma?

Prognosis in patients with renal cell carcinoma

In general, the prognosis and prediction of outcomes after treatment for RCC is generally based on tumor-specific factors (size of tumor, extent of spread, and histology) and patient-specific factors (comorbidities, clinical status, and performance status). Based on large studies of patients with RCC, prognostic scoring systems have been developed and validated.

Stage Size Grade and Necrosis (SSIGN) scoring system for clear cell RCC; emphasis on histologic/pathologic features of clear cell RCC

Fuhrman Nuclear Grading System for RCC (primarily for clear cell type; this is a histologic/pathologic grading system)

Tumor Node Metastasis staging system:

This system is used to give general prognostic information based on the extent of tumor burden (local and distant). This system is used to evaluate survival up to 5 years post-diagnosis, based on the stage at the time of diagnosis.

This system is perhaps the most widely used and most well validated scheme for prognostic stratification. This system is based on clinical factors (performance status and laboratory data) and was developed based on outcomes of patients with advanced RCC. The system has also been validated by the Cleveland Clinic Foundation. Five factors are used to estimate survival in patients with advanced disease:

LDH > 1.5 x the upper limit of normal

Corrected serum calcium > 10 mg/dl

Hemoglobin < the lower limit of normal

No prior nephrectomy

Karnofsky performance status < 80 (SEE )

Based on these five factors, 3 risk categories are determined and correlate with survival data.

This staging system incorporates histologic grade (SEE: FUHRMAN GRADE) and replaces the Karnofsky performance status with the ECOG-PS (Eastern Cooperative Oncology Group Performance Status) (SEE:ECOG-PS). The 1997 TNM stage is used and 5 categories were developed to predict 2 and 5 year survival for RCC. Five stages are delineated, each with its own 2 and 5 year survival estimates. This system is base on survival post-nephrectomy and included patients with metastatic and non-metastatic disease. The system is limited in its applicability as the data predates modern therapeutic modalities. However, it may be superior to clinical stage alone for predicting survival in patients with RCC (reference 23; Table 2, page 1652).

The use of this scoring system is specific for clear cell RCC (the most common subtype). It uses a scoring system based on histologic features of the tumor and predicts outcomes (particularly 10 year cancer-specific survival). This system was developed at the Mayo Clinic and has since been validated at other centers. A score is given from 0-15 based on tumor characteristics (pathologic tumor category, nodal status, metastasis category, tumor size, tumor grade, and tumor necrosis).

This system estimates a ten year survival of 97% for a score 0-1, 50% for a score of 5, and less than 5% for a score >/= 10.

Fuhrman Nuclear Grading System for Kidney Cancer:

It is suggested that a nuclear grading system may be a unifying concept, applicable to all tumors of any size, pattern, or cell type. However the Fuhrman system (Table 2) has been best described in ccRCC and may not be as predictable in non-ccRCC such as papillary and chromophobe types.

Nuclear grade may reflect the biologic potential of a tumor and predict the long-term activity of it. However, the value of this grading system may be limited by inter- and intra-observer variation in the interpretation. Therefore, the best predictive value results when experienced pathologists and standardized techniques are implemented. Although this grading system has been included in multifactorial prediction models, it has been used as an independent factor as well.

Studies validating the Fuhrman grading system have, by convention, combined grade I and II to establish a 3 grade system which is now accepted by the American Joint Committee on Cancer (AJCC).

Limitations and controversies in the use of prognostic scoring shemes:

The greatest limitation to these schemes is that they were developed before the modern era of targeted thereapies for RCC. In addition, many of the schemes were developed in studies that consisted primarily of patients undergoing surgery which may lead to selection bias and may not be applicable over broad patient presentations.

At least one study validated the MSKCC model for predicting prognosis in patients treated with the VEGF-targeted therapies sunitinib, sorafenib, and bevacizumab (SEE SECTION ON TREATMENT: TARGETED THERAPIES). In this model 2 additional factors were noted to be significant ; neutrophil count > the upper limit of normal and platelet count > the upper limit of normal. Based on this modified model 2 year survival for 3 groups is estimated:

Favorable (0 adverse factors): 75%

Intermediate (1 or 2 adverse factors): 53%

Poor (3-6 adverse factors): 7%

Prognostic value of cell type:

The following histologic subtypes are recognized by the American Joint Committee on Cancer.

Clear cell

Papillary

Chromophobe

Collecting duct

Unclassified

Recent studies suggest a prognostic significance when comparing cell types. Most notable is a suggested worse prognosis with an increased cancer-specific death and rate of distant metastasis with the clear cell type. Previous multivariate analyses have failed to find an independent predictive value to cell type. However, these studies were mostly retrospective and used multiple pathologists at various sites.

TNM staging systems for kidney cancer are published by the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC).

The Karnofsky Performance Status is a measure of physical function which ranges from normal with no incapacities and the ability to carry out normal activity and work, to moribund. A scoring system from 0-100 on a 10 point increment scale us uses with 100 being the best functional capacity and 0 representing death.

80-100 represents those able to carry on normal activity and work without special care needs

50-70 represents those unable to work but with the capacity to live at home and care for most personal needs with various degrees of assistance needed

0-40 represents those unable to care for themselves with the requirement of institutional or hospital level care; this may also represent a rapidly progressive disease

The ECOG Performance Scale ranges from fully active without performance restrictions to completely disabled and unable to care for ones self, with confinement to bed or chair. This model gives patients a score from 0-4 with worsening functional capacity in ascending order.

How to utilize team care?

Patients with RCC require a multidisciplinary team in the work-up and management of their disease. This is a very unique and challenging form of cancer, especially when it is advanced or recurrence occurs. For isolated small tumors which may be curable by surgery alone, a complete multidisciplinary team may not be necessary. However, for advanced disease where there may be combined surgical and immunotherapy or molecular targeted therapy, involvement of multiple subspecialties and ancillary teams may be necessary.

This would typically include a urologist, medical oncologist, and nephrologist (particularly if the patient has CKD before treatment or if renal complications occur due to treatment). In addition, if ablative therapy is entertained. a surgeon subspecialized in ablative treatment or interventional radiologist may be needed. Disease invading the central venous system may require vascular or cardiothoracic surgery. In all cases specialized nurses in the various fields will be necessary to help carry out treatment and follow up protocols.

Given the complexity of some of the newer therapies and their various side effects, clinical pharmacists are helpful in guiding prescribing physicians and counseling patients. Other invaluable members of the team are the pathologists and diagnostic radiologists, who not only interpret the initial diagnostic studies, but are involved in follow-up studies and surveillence protocols. Lastly, as with all disease states in which there may be no cure, or where there is progression with a risk of disease-related suffering, a palliative care team may be necessary.

Are there clinical practice guidelines to inform decision making?

Clinical Guidelines for the Treatment of Renal Cell Carcinoma

Treatment of Stage I-III RCC

Most guidelines support a surgical approach for the management of stageI-III disease. Nephron-sparing surgery with partial resection is preferred in cases where it is feasable. Otherwise radical nephrectomy is done. In non-surgical candidates with smaller (stage IA) tumors,thermal ablation can be considered. In the larger IB tumors which are not amenable to thermal ablation, partial or radical nephrectomy is recommended. In stage II and III tumors radical nephrectomy is required for the best cancer associated outcomes. Note that in any stage of disease, based on clinical factors and patent wishes, surveillence can be instituted with plans to guide therapy based on future progression or stability of disease. However, for patients to make such decisions,they need to be informed according to current standards and guidelines.

Treatment of Stage IV (metastatic RCC

Several guidelines have been established from various societies in Europe and North America for the treatment of metastatic (Stage IV) renal cellcarcinoma. Because most of the experience has been with ccRCC, the guidelines reflect treatment of this subtype. Although there is a great deal of overlap and consensus between guidelines some differences exist, which results in a multitude of options. The recommendations are based on prognosis and prior treatment.

North American Guidelines:

NCCN (National Comprehensive Cancer Network)

CCO (Cancer Care Ontario)

European Guidelines:

ESMO (European Society of Medical Oncology)

EAU (European Association of Urology)

EORTC-GU (Europen Organization for Research and Treatment of Cancer Genitourinary Group)

SOGUG (Spanish Oncology Genitourinary Group)

AFU (French Urology Association)

UK (United Kingdom Consensus Guidelines)

The recommendations from NCCN are more broad and perhaps complex than all of the other recommendations, giving several options for therapy in each of 4 categories prognosis/prior treatment (1st line good to intermediate prognosis, 1st line poor prognosis, 2nd line with prior cytokine therapy, and 2nd line with prior VEGF-targeted therapy). These guidelines grade the recommendations based on the level of clinical evidence supported in the literature. In general, the best evidence and primary recommendations match those of the other organizations.

All of the other guidelines recommend the following basic treatment stragegies based on 1st or 2nd line therapy and prognosis:

1st line with good to intermediate prognosis: Sunitinib or Bevacizumab + IFN-α